The overall objective of Dr. O'Donnell's Genomic Epidemiology of Cardiovascular Disease research program during FY 2015 is to investigate the epidemiology and genetic/genomic epidemiology of subclinical and clinical atherosclerotic cardiovascular disease (CVD) and its risk factors, including hemostatic and thrombotic risk. The longer term goal is to translate these results to prediction, prevention and personalization of CVD medicine. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and collaborative DNA and RNA sequencing projects. Dr. O'Donnell is the Associate Director of the NHLBI's Framingham Heart Study (FHS), Scientific Director and Steering Committee Chair of the NHLBI's Framingham Heart Study (FHS) SHARe Program, co-founder and Steering Committee Co-chair of the CHARGE Consortium, and Co-Director of the HeartGO Consortium of the NHLBI GO Exome Sequencing Project (ESP). Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3, and secondarily of participants of several collaborating cohort studies. Phenotyping: Phenotyping consisted of: (a) risk factor measures from usual clinical exams (lipids, blood pressure, anthropometric and physical examination); (b) biomarkers from peripheral blood (eg, C-reactive protein, fibrinogen, von Willebrand factor); (c) imaging measures of subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging (MDCT) in 3500 Offspring and Generation 3 subjects; carotid intimal medial thickness (CIMT) and carotid plaque by B-mode ultrasonography in 3800 Offspring: aortic plaque, LV mass by cardiovascular magnetic resonance imaging (CMRI) in 1800); (d) clinical CVD outcomes (myocardial infarction; coronary heart disease; CVD) adjudicated by a physician endpoint validation committee; (e) gene expression of lymphocyte- and platelet-derived RNA using rtPCR, whole genome RNA profiling (Affymetrix Exon Array), and next-generation RNA sequencing. Genotyping in SHARe and resequencing: Genotyping derived from dense genomewide SNP scans including a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH and to 40 million SNPs from the 1000 Genomes Project. Additional SNP genotyping was conducted using various platforms including 250K functional exon variants on the exome chip (Illumina). Next-Generation sequencing including targeted gene region sequencing, whole exome sequencing, and whole genome sequencing, is being conducted in several US genome centers. Statistical association and linkage methods: Statistical association analyses of genomewide association (GWA) of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate; additionally, family based association testing. Statistical linkage analyses were conducted using SOLAR. Testing for association of low frequency variants and burden of rare variants was conducted using various tests. Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we combined data within a consortium of prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. In silico replication meta-analysis is performed. Research Accomplishments for Major Projects Directed by Dr. O'Donneell in FY 2015: 1. Genetic determinants of myocardial infarction: In conjunction with the Exome Sequencing Program MI Working Group (co-chaired by Dr. O'Doonnell and Dr. Kathiresan), we reported on variants in the APOA5 gene on triglyceride level and myocardial infarction in the largest exome sequencing project for myocardial infarction. 2. Genetic determinants of hemostatic factors and other biomarkers: In the CHARGE Consortium, we published the results of an association study of exome chip variation with factor VII, vWF and Factor VIII. 3. Genetic determinants of subclinical atherosclerosis and risk factors: In conjunction with the CHARGE Consortium, we contributed to a publication of the 1000Genomes imputed GWA analysis of coronary artery calcification (in preparation) and carotid IMT (in preparation) as well as exome chip analysis of coronary calcification and carotid IMT (in preparation). 4. Genetic determinants of myocardial infarction/coronary heart disease: We contributed to a publication on the 1000Genomes imputed GWA analysis for the largest meta-analysis of coronary artery disease to date and a second publication on association of height genes with MI. 5. Epidemiology of the risk of subclinical disease, metabolomics and genetics: In the CHARGE Consortium, we have completed a GWAS for incident MI (in press). We have submitted a manuscript on the association of rare and common SNP variation with family history of premature CVD (submitted). We are developing an updated Framingham CHD risk score that includes family history in the model (in preparation). We have submitted a papar on exome chip variation of metabolomic signatures in the Framingham Heart Study. Selected references (out of >40 publications published/in press in PubMed September 2014 to September 30 2015): 1: Tsao CW...O'Donnell CJ. Left ventricular structure and risk of cardiovascular events: A Framingham Heart Study cardiac magnetic resonance study. J Am Heart Assoc 2015;4(9). 2: Laugsand LE...O'Donnell...Jensen MK. Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies. Atherosclerosis 2015;243(1):44-52. 3: CARDIoGRAMplusC4D Consortium. A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015(epub ahead of print). 4: Pursnani A...O'Donnell CJ, Hoffmann U. Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events. JAMA 2015;314(2):134-41. 5: Huffman JE...O'Donnell CJ, Smith NL. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood 2015;126(11):e19-29. 6: Cheng S...O'Donnell CJ...Wang TJ. Distinct metabolomic signatures are associated with longevity in humans. Nat Commun 2015;6:6791. 7: Nelson CP...O'Donnell CJ...Samani NJ; CARDIoGRAM+C4D Consortium. Genetically determined height and coronary artery disease. N Engl J Med 2015;372 (17):1608-18. 8: van der Lee SJ...O'Donnell CJ...van Duijn CM. PLD3 variants in population studies. Nature 2015;520(7545):E2-3. 9: Amendola LM...O'Donnell CJ...Jarvik GP. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 2015;25(3):305-15. 10: Wessel J...O'Donnell CJ...Goodarzi MO. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 2015;6:5897. 11: Do R...O'Donnell CJ, Altshuler D, Gabriel S, Kathiresan S. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature;518(7537):102-6. 12: Myocardial Infarction Genetics Consortium Investigators, Stitziel NO...O'Donnell...Kathiresan S. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 2014;371(22):2072-82.